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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism (Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls (P <.0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.
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PMID:Developmental regression and mitochondrial dysfunction in a child with autism. 1882 80

Searching for a peripheral biological marker for schizophrenia, we previously reported on elevated mitochondrial complex I 75-kDa subunit mRNA-blood concentrations in early onset schizophrenia (EOS). The aim of this study was to further evaluate the utility of this gene as a potential marker for schizophrenia. Both-schizophrenia and autism-are suggested to be neuronal maldevelopmental disorders with reports of mitochondrial dysfunction and increased oxidative stress. Therefore we have investigated the expression levels of mitochondrial complex I 75-kDa subunit mRNA in whole blood of children with autistic spectrum disorder (ASD) and a group of adolescent acute first-episode EOS patients in comparison to matched controls. We have found that compared to the respective controls only the group of EOS patients-and not the ASD group-showed a significantly altered expression of the complex I 75-kDa subunit mRNA. Although further studies are necessary to test for the specificity of this marker, our findings point to the potential use of the mitochondrial complex I as a biomarker for schizophrenia.
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PMID:Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. 1989 76

Mitochondrial disorders are usually associated with defects of 1 or more of the 5 complexes (I to V) of the electron transport chain, or respiratory chain. Complex I and IV are the 2 most frequent abnormalities of the electron transport chain in humans. The authors report the case of a 12-year-old boy with dysmorphic facies, mental retardation, autism, epilepsy, and leg weakness. Buccal swab electron transport chain analysis revealed severe decrease in complex IV and mild reduction in complex I activity levels. Chromosomal microarray studies, using array-based comparative genomic hybridization, revealed a 1-Mb deletion in the 5q14.3 region. This case illustrates that this deletion can be associated with complex I and IV deficits, hence manifesting as a mitochondrial disease. It could be hypothesized that genes that either encode or regulate the expression and/or assembly of complex IV or I subunits are located within the deleted region of 5q14.3.
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PMID:5q14.3 deletion manifesting as mitochondrial disease and autism: case report. 2153 14

Mitochondria play important roles in generation of free radicals, ATP formation, and in apoptosis. We studied the levels of mitochondrial electron transport chain (ETC) complexes, that is, complexes I, II, III, IV, and V, in brain tissue samples from the cerebellum and the frontal, parietal, occipital, and temporal cortices of subjects with autism and age-matched control subjects. The subjects were divided into two groups according to their ages: Group A (children, ages 4-10 years) and Group B (adults, ages 14-39 years). In Group A, we observed significantly lower levels of complexes III and V in the cerebellum (p<0.05), of complex I in the frontal cortex (p<0.05), and of complexes II (p<0.01), III (p<0.01), and V (p<0.05) in the temporal cortex of children with autism as compared to age-matched control subjects, while none of the five ETC complexes was affected in the parietal and occipital cortices in subjects with autism. In the cerebellum and temporal cortex, no overlap was observed in the levels of these ETC complexes between subjects with autism and control subjects. In the frontal cortex of Group A, a lower level of ETC complexes was observed in a subset of autism cases, that is, 60% (3/5) for complexes I, II, and V, and 40% (2/5) for complexes III and IV. A striking observation was that the levels of ETC complexes were similar in adult subjects with autism and control subjects (Group B). A significant increase in the levels of lipid hydroperoxides, an oxidative stress marker, was also observed in the cerebellum and temporal cortex in the children with autism. These results suggest that the expression of ETC complexes is decreased in the cerebellum and the frontal and temporal regions of the brain in children with autism, which may lead to abnormal energy metabolism and oxidative stress. The deficits observed in the levels of ETC complexes in children with autism may readjust to normal levels by adulthood.
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PMID:Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. 2125 Sep 97

Both copy number changes in the 22q13 region and mitochondrial disease have been associated with autism spectrum disorder. In this report, for the first time, a girl with autism spectrum disorder is described who exhibits both mitochondrial disease and a 22q13.1-33 duplication. This child demonstrated hypotonia, developmental delays, growth deficiency, microcephaly, dysmorphic facial features, and white matter abnormalities, consistent with previous cases of 22q13 region duplication. The patient also demonstrated a unique pattern of electron transport chain abnormalities with marked decreases in complex II and II/III in fibroblasts and complex I/III and II/III in muscle tissue. The 22q13.1-33 region contains 6 genes associated with mitochondrial function. Thus, disruption of this chromosomal region could cause many of the clinical findings in this child through disruption of mitochondrial function. Therefore, a mitochondrial workup should be considered in individuals with copy number changes within the 22q13 region, such as those with Phelan-McDermid syndrome.
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PMID:Mitochondrial disease in 22q13 duplication syndrome. 2237 73

Voltage Dependent Anion Channel (VDAC) in the cell membrane transports important molecules and ions across the cell membrane. It was recently shown that VDAC also acts as a trans membrane NADH dehydrogenase. A recent study showed that autistic children have increased antibodies to VDAC proteins and such a binding inhibits both the transport and dehydrogenase activities of VDAC. The derived function of VDAC, therefore, might underlie the development of autism. It has also recently been shown that the dehydrogenase in erythrocyte membranes requires coenzyme Q. Since the plasma membrane oxidase is not in erythrocyte membranes, the coenzyme Q requirement must be for VDAC. This is consistent with sensitivity of the dehydrogenase to SH inhibitors. This is a novel site for coenzyme Q function but it has an analogy with the Q requirement for the mitochondrial uncoupler protein and the permeability transition pore.
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PMID:Evidence for a relation between plasma membrane coenzyme Q and autism. 2374 16

Maternal immune activation (MIA) is a potential risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). In rodents, MIA results in changes in cytokine profiles and abnormal behaviors in the offspring that model these neuropsychiatric conditions. Given the central role that mitochondria have in immunity and other metabolic pathways, we hypothesized that MIA will result in a fetal imprinting that leads to postnatal deficits in the bioenergetics of immune cells. To this end, splenocytes from adult offspring exposed gestationally to the viral mimic poly(I:C) were evaluated for mitochondrial outcomes. A significant decrease in mitochondrial ATP production was observed in poly(I:C)-treated mice (45% of controls) mainly attributed to a lower complex I activity. No differences were observed between the two groups in the coupling of electron transport to ATP synthesis, or the oxygen uptake under uncoupling conditions. Concanavalin A- (ConA-) stimulated splenocytes from poly(I:C) animals showed no statistically significant changes in cytokine levels compared to controls. The present study reports for the first time that MIA activation by poly(I:C) at early gestation, which can lead to behavioral impairments in the offspring similar to SZ and ASD, leads to long-lasting effects in the bioenergetics of splenocytes of adult offspring.
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PMID:Gestational exposure to a viral mimetic poly(i:C) results in long-lasting changes in mitochondrial function by leucocytes in the adult offspring. 2417 10

Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.
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PMID:AMPD1 functional variants associated with autism in Han Chinese population. 2515 76

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder.
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PMID:Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder. 2649 53

Phelan-McDermid Syndrome (PMS), which is defined by a deletion within 22q13, demonstrates significant phenotypic variation. Given that six mitochondrial genes are located within 22q13, including complex I and IV genes, we hypothesize that mitochondrial complex activity abnormalities may explain phenotypic variation in PMS symptoms. Complex I, II, II + III and IV activity was measured in 51 PMS participants. Caretakers completed questionnaires and provided genetic information through the PMS foundation registry. Complex activity was abnormal in 59% of PMS participants. Abnormalities were found in complex I and IV but not complex II + III and II activity, consistent with disruption of genes within the 22q13 region. However, complex activity abnormalities were not related to specific gene deletions suggesting a "neighboring effect" of regional deletions on adjacent gene expression. A specific combination of symptoms (autism spectrum disorder, developmental regression, failure-to-thrive, exercise intolerance/fatigue) was associated with complex activity abnormalities. 64% of 106 individuals in the PMS foundation registry who did not have complex activity measured also endorsed this pattern of symptoms. These data suggest that mitochondrial abnormalities, specifically abnormalities in complex I and IV activity, may explain some phenotypic variation in PMS individuals. These results point to novel pathophysiology mechanisms and treatment targets for PMS patients.
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PMID:Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome. 2682 10


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